3D spheroid model reveals enhanced efficacy of mannose-decorated nanoparticles for TB treatment.

Aims: Tuberculosis (TB), caused by Mycobacterium tuberculosis remains a significant global health challenge aggravated by drug-resistant strains and prolonged treatment regimens. Innovative strategies to enhance treatment efficacy, improve patient adherence, and reduce adverse effects are urgently required.

Methods: We explored a combination therapy using bedaquiline and pretomanid encapsulated in polymeric nanoparticles (pNPs). Further, active targeting was achieved through mannose-decorated nanoparticles (Man-pNPs) for macrophage-specific delivery. The drug-loaded pNPs and Man-pNPs were spray-dried into dry powder particles to improve drug solubility and enable local lung delivery via inhalation. Man-pNPs were prepared to target macrophages, wherein TB bacteria reside.

Results: Formulations exhibited high drug loading and excellent aerosolization performance (MMAD 1-5 µm, FPF > 75%) for pNPs and Man-pNPs. Man-pNPs formulation enhanced macrophage targeting via receptor-mediated endocytosis and phagocytosis, improving bacterial inhibition. Man-pNPs demonstrated similar MIC in vitro and enhanced intracellular M.tb inhibition compared to free drug combination and pNPs. In addition, a TB spheroid model was developed for formulation screening, mimicking granulomas' physiological conditions. Man-pNPs formulation showed superior intracellular bacterial inhibition in TB spheroid model compared to free drug combination and pNPs.

Conclusion: This research underscores the potential of combination therapy, particulate-based inhaled drug delivery, and active targeting to advance efficient and patient-friendly TB treatments.